1. Field of the Invention
This invention is for a pharmaceutical compound containing ginsenoside Rg3 and/or its pharmaceutically acceptable salts as an active ingredient for preventing and treating Hepatitis C infection
2. Description of the Related Art
Hepatitis C virus (referred as “HCV” hereafter) infection is mainly transmitted via transfusion and community-acquired infection. It is also reported that 70% of kidney dialysis may transmit the HCV infection. It is known that approximately 20% of the infected patients, once infected with HCV, may develop acute hepatitis accompanying liver cirrhosis which may convert to liver cancer in five (5) years (Davis et al, New. Engl. J. Med., 321, 1501, 1989; Alter et al, in Current Pespective in Hepatology, p 83, 1989). This high infection rate of chronic hepatitis is a rare case in RNA infections and it tells that the HCV plays a big role in liver cancer transmission. Since very thorough examinations are conducted for blood samples recently, HCV infection via transfusion is well controlled. However, the HCV infection via community-acquired infection cannot yet be controlled, it appears to be a serious issue world-widely.
According to recent scientific reports, approximately 200 million people are infected with HCV world-widely and 4.5 million people are presumed to be infected with HCV in the USA (it is assumed that the number of 4.5 million could be raised up to 15 million). In Europe, at least 5 million people are presumed to be hepatitis C patients.
Up to now, neither a satisfactory vaccine against Hepatitis C nor an effective therapeutic agent to treat Hepatitis C has yet been available. Therefore, numerous pharmaceutical companies and research institutes all over the world keep trying to invent an effective Hepatitis C treating agent. Compared with Hepatitis B, HCV patients are evenly distributed across the world and demonstrate much higher rate to convert to liver cirrhosis and then to liver cancer. In addition, Hepatitis C also demonstrates a higher rate to convert to chronic hepatitis, and so studies to identify the mechanism for converting to chronic hepatitis are still going on. Hepatitis C virus can be transmitted not only by transfusion but also by intravenous drug injection and by printing tattoos. However, its major transmission is made by direct blood contacts. Once infected with HCV, most of the infected patients may progress to chronic hepatitis and then further to liver cirrhosis and liver cancer. Therefore, it is urgently requested to develop an effective vaccine and a therapeutic agent to treat Hepatitis C. There are many different genotypes available and mutations occur among HCV strains, and so HCV re-infection or co-infection may occurs concurrently once chronic hepatitis is developed by HCV. This is why an effective vaccine invention against HCV is difficult.
The current Hepatitis C treatment is conducted using a combination therapy with Interferon-α with Ribavirin. However, this treatment demonstrates very low rate of cure and brings severe side effects. About 25% of Hepatitis C patients do not respond to Interferon-α and another 25% of patients are apt to setback to the disease after responding temporarily to the medicine. The rest 50% of patients maintain normal ALT level and remain HCV RNA negative even after the treatment finished. Furthermore, those 50% of treated patients relapse into it in 3-6 months from the first treatment. In this case, only 25% of Hepatitis C patients show sustained viral response (SVR) and its treatment effect retains at most six months in those patients. Furthermore, among the six different Hepatitis C virus genotypes, the most common genotype 1b does not respond to Interferon-α so well compared to genotype 2 or genotype 3. In case of combination therapy with Interferon-α and Ribavirin is administered, the treatment is made with double effect. When Ribavirin alone is treated, the treatment effect is not so good and rather brings side effects such as anemia resulted from erythroclasis. So, Ribavirin is prescribed only when a patient does not respond to Interferon-α or Hepatitis C is relapsed. So far, an effective antiviral agent that is specifically targeted to hepatitis C virus with no setbacks/relapsing has not yet been developed.
RNA genome was first isolated from HCV through a molecular cloning in 1989 (Choo, Q-L, et al., 1989, Isolation of a cDNA clone was derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359-362). Since then, molecular biological approaches to HCV have been made. However the approaches were limited due to lacks of both efficient cell culture system and animal model. But recently, a hepatoma cell line replicating HCV RNA replicon has been established stably to overcome the limitation (Lohmann, V., F. Korner, J-O Koch, U. Herian, L. Theilmann, R. Bartenschlager, 1999, Replication of subgenomic hepatitis c virus RNAs in a hepatoma cell line. Science 285:110-113). The HCV RNA replicon is divided into two categories; 1) full length replicon containing whole HCV gene and 2) subgenomic replicon in which structural proteins are excluded. The HCV RNA replicon is bicistronic replicon containing HCV 5 end, HCV IRES, neomycin resistant gene (neomycin transferase gene), and EMCV (encephalomyocarditis virus) IRES. HCV nonstructural proteins are composed of sequences comprising NS3-NS5B and HCV 3′ end (untranslational region). HCV replicons against each genotype of HCV are developed (identified), which help different case studies.
JFH-1 virus (Japanese Fulminant Hepatitis-1 Virus) was first isolated from 32 year-old Japanese male patient with acute liver malfunction in 2005 (Wakita et al.), and is 2a genotype of Hepatitis C virus. JFH-1 infected with Huh7.5.1 liver cell line can replicate infectious virus and thus it is applicable to estimate anti-HCV agent or to study HCV pathology.
Ginseng has been used as a tonic agent for life extension in oriental medicine (Yun, 2001). Ginseng has been reported to have activities of treating disorders related to central nerves system, cardiovascular disease, endocrinal disorder, immune disease and aging disorder, and has been using as thermogenics, biological controller and the like (Liu and Xiao, 1992; Seong et al., 1995; Kitts et al., 2000; Bae et al., 2006). Recently, it is reported that Ginseng shows anticancer activities for appendix adenocarcinoma, B16 malignant melanoma (Mochizuki et al., 1995; Iishi et al., 1997; Liu et al., 2004), and inhibits prostate cancer cell growth (Keum et al., 2003; Kim et al., 2004) and ovary cancer (Nakata et al., 1998).
It is known that one of major active ingredients is ginsenoside (Attele et al., 1999; Yuan and Wu, 2002). Ginseng is generally comprised of 30 more ginsenosides, and each of them shows various pharmacological activities (Tanaka et al., 1986; Banthorpe, 1994; Yue et al., 2007). It has been reported that ginsenoside Rg3 especially exhibits both strong anticancer activity and anti-metastasis activity (Mochizuki et al., 1995; Shinkai et al., 1996; lishi et al., 1997; Liu et al., 2000; Pan et al., 2002; Chen et al., 2003, 2008; Keum et al., 2003; Korean Patent Publication No. 10-2011-0106006; Kim et al., 2004; Panwar et al., 2005; Wang et al., 2006, 2007; Zhang et al., 2006; Xu et al., 2007; Kwon et al., 2008; Lu et al., 2008; Luo et al., 2008).
Red ginseng (Ginseng Radix Rubro), is obtained via a steam processed treatment at 98˜100° C. for 2˜3 hours. During the steam treatment processes, the amount of ginsenosides increases significantly (Kim et al., 2000; Wang et al., 2006), and such processed ginseng (red ginseng) with enhanced ginsenosides shows superior pharmacological activities than a raw ginseng (Jung and Jin, 1996; Wang et al., 2006).
On the other hand, as a description of ginsenosides, Korean Patent Publication No. 10-2012-0031588 discloses pharmaceutical composition for enhancing bone formation comprising 20(S)-ginsenoside Rh2 as an active ingredient, Korean Patent Publication No. 10-2011-0122580 discloses pharmaceutical composition for treating autoimmune disease comprising ginsenoside I as an active ingredient, Korean Patent Publication No. 10-2011-0117760 discloses pharmaceutical composition for anti-stress comprising red ginseng extract which has enhanced ginsenoside Rg3 content as an active ingredient, and Korean Patent Publication No. 10-2011-0057895 discloses skin composition for external application for increasing formation of hyaluronic acids comprising ginsenoside Re and ginsenoside compound K. However, it has not been known that ginsenoside Rg3 may be used as an agent for preventing or treating Hepatitis C.
As a final result of hard working studies to find a safe and no side effect hepatitis C preventing and treatment product, these inventors have found that ginsenoside Rg3 isolated from red ginseng has excellent activities of antiviral and apoptosis against Hepatitis C virus cells, reducing TNF-α and thioredoxin levels significantly, and increasing phospho-NFκB. It also shows the same effect of PegInterferone alpha-2b(PegIFN a-2b, Hepatitis C therapeutics), and has no cytotoxicity. Therefore, the inventors completed this invention by confirming the ginsenoside Rg3 may be used safely as a pharmaceutical composition or a health food composition for preventing or treating Hepatitis C.